Effects of naloxone on glucose level in the hepatic venous plasma in the rat

1. The effect of opioid receptor blockade by naloxone in vivo on hepatic venous plasma glucose concentration in rats was investigated. 2. The plasma glucose levels in naloxone-injected animals (10 mg/kg) were higher than in the control animals (P less than 0.05). 3. At the lower dose of naloxone (2 mg/kg) the resulting plasma glucose concentration did not differ significantly from control (P greater than 0.1). 4. It is concluded that endogenous opioids may moderate the regulation of basal glucose levels in the rat.     

Opiate receptor binding—enhancement by opiate administration in vivo

Administration of opiate agonists and antagonists to mice produces a dose-dependent 50–100 per cent enhancement of stereospecific [³H]dihydromorphine or [³H]naloxone binding to brain homogenates within 5 min. Three opiate antagonists are 10–1000 times more potent in eliciting this increase in binding than their structurally analogous agonists. Naloxone, the antagonist with the least agonist activity, is the most potent drug in producing receptor enhancement. Implantation of morphine pellets in mice increases receptor binding 30–100 per cent for 2 108 hr with no time-dependent trend. Drug-induced receptor binding enhancement appears to involve an increase in number of binding sites rather than a change in receptor affinity. Sodium, which increases binding of opiate antagonists in normal mouse brain homogenate, fails to increase binding of [³H]naloxone in homogenates derived from naloxone-injected mice.     

Antidiabetic and antiobesity effects of a highly selective β3-adrenoceptor agonist (CL 316,243)

A third β-adrenoceptor subtype has been cloned form the rat, mouse, and human genomes. The presence of these receptors primarily on adipose tissue has raised the possibility that β₃-adrenoceptor selective agonists may be useful antiobesity agents. CL 316,243 is a highly selective β₃-agonist; it has a <30,000 to 1 β₃-to-β₁-adrenoceptor selectivity ratio and a 10,000 to 1 β₃-to-β₂-adrenoceptor selectivity ratio in in vitro functional assays. In vivo, animals were treated with CL 314,698, a diester prodrug of CL 316,243, which is rapidly converted to CL 316,243. In obese (ob/ob) and diabetic (db/db) mice, treatment with CL 314,698 reduced their hyperglycemia to the euglycemia of their lean littermates, and decreased plasma insulin levels. In obese mice, the compound also caused decreased weight gain despite increased food consumption, and the decreased weight was due to loss of fat while lean body mass was spared. CL 314,698 treatment also improved both glucose and insulin tolerance in obese mice, suggesting that it decreased insulin resistance. CL 314,698 also prevented further weight gain, without affecting food consumption, in rats previously made obese by feeding a high fat diet. The compound reduced plasma insulin and triglyceride levels, and reduced fat pad weights, while having no effect on plasma glucose, cholesterol, thyroxine, or T₃ levels or on skeletal muscle weight. Decreased weight gain without decreased food consumption suggested that CL 316,243 stimulated thermogenesis. Treatment of obese mice for 3 weeks with CL 316,243 increased thermogenesis by 45% as measured by indirect calorimetry. Thus, CL 316,243 is a potent, β₃-adrenoceptor selective agonist with thermogenic, antidiabetic, and antiobesity properties in several models of non-insulin dependent diabetes and obesity.     

Role of alpha 1- and alpha 2-adrenoceptors in catecholamine-induced hyperglycaemia, lipolysis and insulin secretion in conscious fasted rabbits.

1. In conscious fasted rabbits an intravenous infusion of clonidine (2 micrograms kg-1 min-1) induced hyperglycaemia. The increase in blood glucose was accompanied by an inhibition of insulin secretion and basal lipolysis. 2. Yohimbine infused at a rate of 20 micrograms kg-1 min-1 suppressed clonidine-induced hyperglycaemia and blocked the inhibitory effect on insulin secretion mediated by the alpha 2-adrenoceptor agonist. 3. The intravenous infusion of amidephrine (10 micrograms kg-1 min-1) induced an increase in insulin secretion in the absence of patent hyperglycaemia. Prazosin, 0.3 mg kg-1 s.c. selectively antagonized the effect of amidephrine on insulin secretion. 4. Isoprenaline infusion (4.4 micrograms kg-1 min-1) evoked a significant increase in blood glycerol and immunoreactive insulin plasma levels. Both responses were clearly attenuated when alpha 2-adrenoceptors were simultaneously stimulated by selective (clonidine) and less selective (phenylephrine, 20 micrograms kg-1 min-1) agonists. 5. Amidephrine infusion did not induce appreciable changes in blood glycerol nor did it modify, isoprenaline-induced lipolytic response. 6. Simultaneous infusion of isoprenaline and amidephrine induced a remarkable increase in insulin secretion. 7. It is concluded that in normal fasted rabbits stimulation of alpha 2-adrenoceptors depresses basal and beta-adrenoceptor mediated lipolysis and insulin secretion. On the other hand, selective stimulation of alpha 1-adrenoceptors does not affect lipolysis but induces insulin release. Simultaneous stimulation of alpha 1- and beta-adrenoceptors potentiates the insulin secretory response.     

Effects of neonatal sympathetic denervation on amylase secretion in the adult rat parotid gland: Difference in β1- and β2-adrenoceptor response

Changes in amylase secretion and cyclic AMP accumulation in response to various secretagogues were studied in parotid glands of adult rats subjected to neonatal sympathetic denervation by unilateral excision of the superior cervical ganglion. Denervation decreased the gland content of amylase and both basal and the stimulated levels of cyclic AMP were elevated. The secretory cells of neonatally devervated glands exhibited enhanced maximal enzyme discharge in response to β-adrenoceptor agonists. However, the selective β₁-agonist, prenalterol, was not effective in this respect whereas an enhanced maximal secretory response to the β₂-selective agonist, terbutaline, was particularly prominent. DBcAMP was also more efficient in inducing amylase release from the denervated gland. The results of the present study demonstrate that the usual dominance of the β₁-adrenoceptor subtype in eliciting amylase 3elease is lost, implying that the differentiation of the β-adrenoceptor into its subtypes is altered by neonatal sympathetic denervation.     

Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus: focus on bile acid sequestrants

Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic β-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2 diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, α-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT-777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin-resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP-1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, α-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion.     

Effects of the 5-HT1C/5-5-HT2 receptor agonists DOI and alpha-methyl-5-HT on plasma glucose and insulin levels in the rat

Administration of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI, 0.125-2.0 mg/kg i.v.) triggered dose-dependent increases in plasma glucose; plasma insulin levels remained unchanged. Pretreatment with the 5-HT1C/5-HT2 receptor antagonists LY 53857, ritanserin, or the mixed 5-HT2/alpha 1-adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT1C receptor agonists/5-HT2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-trifluoromethyl)phenyl)piperazine level (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The alpha 2-adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, Whilst the alpha 1-adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT1C/5-HT2 receptor agonist alpha-methyl-5-HT (0.5-1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished alpha-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT2 receptors, but not 5-HT1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT2 receptors may affect glycemia.     

α2-adrenoceptor regulation of blood glucose homeostasis

The α(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. α(2A)-Adrenoceptors on pancreatic β-cells inhibit insulin secretion, and α(2A)-adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human α(2A)-adrenoceptor gene polymorphisms that influence α(2A)-adrenoceptor expression and function have been described. Increased α(2A)-adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of α(2)-adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished α(1)- and β-adrenoceptor activation. α(2)-Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active α(2A)-adrenoceptors on pancreatic β-cells, but may also enhance sympathoadrenal output. In addition, α(2)-adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The α(2)-adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated α(2)-adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent α(2)-adrenoceptor antagonists. In the treatment of type 2 diabetes, α(2)-adrenoceptor agonists could possibly protect against sulphonylurea-induced hypoglycaemia, and α(2)-adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on α(2A)-adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.     

Amylin and Syndrome-X

A 37 amino-acid peptide, amylin, is secreted from the pancreatic β-cell in response to stimuli similar to those causing insulin secretion. Plasma amylin levels are generally elevated under circumstances where insulin is elevated, including in insulin resistance and in essential (obesity-related) hypertension. Several of amylin's actions may contribute to key features of insulin resistance and the insulin resistance syndrome (Syndrome-X). Actions on muscle glycogen metabolism, Cori cycle activity, and endogenous glucose production may contribute to glucose intolerance while amylin's effects to suppress β-cell secretion could account for the secretory defect observed in early glucose intolerance. Amylin also potently increases plasma renin activity, and could contribute to the hypertension that is associated with obesity and insulin resistance.     

Cholinergic muscarinic effects on insulin release in mice

Insulin secretion and blood glucose homeostasis were studied in mice following administration of cholinergic agonists, antagonists and other possible modifiers of cholinergic insulin secretory mechanisms. It was observed that administration to mice of the cholinergic agonists acetylcholine, carbachol and pilocarpine resulted in an increase in plasma immuno-reactive insulin levels accompanied by a significant fall in blood glucose levels. Nicotine had no effect. Carbachol was found to enhance insulin release in a dose-dependent manner. Muscarinic blockade by atropine or methylatropine totally suppressed carbachol-induced insulin secretion. No blocking effect was accomplished by beta-adrenoceptor blockade. Glucose-induced insulin secretion was not affected by atropine in normal non-fasted mice. In mice fasted for 24 h, however, the insulin response to glucose was impaired by atropine suggesting that the nutritional state is important for cholinergic modulation of glucose-induced insulin response. Pretreatment of animals with the glycogenolytic hydrolase, acid amyloglucosidase, enhanced tolbutamide-induced insulin release but did not influence insulin secretion stimulated by carbachol. Pretreatment with the monoamine oxidase inhibitor, pargyline, plus L-dopa, leading to an intracellular accumulation of dopamine in the insulin cells, totally suppressed carbachol-induced insulin release. It is suggested that, in mice, cholinergic stimulation promotes insulin secretion through activation of muscarinic receptors on the insulin cell. Blockade of these receptors does not influence glucose-stimulated insulin release in the non-fasting state, but may impair the insulin response to glucose after fasting. Cholinergic stimulation of insulin release is inhibited after L-dopa-induced accumulation of dopamine in the insulin cells. In contrast to tolbutamide-induced insulin release cholinergic insulin release is not dependent on acid amyloglucosidase activity.     

Effects of GABAB receptor agonists and antagonists on glycemia regulation in mice

γ-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic β-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2-hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2-hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose-induced insulin secretion and this effect was reversed by coincubation with 1.10(-5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs.     

Effect of some β-adrenoceptor blocking drugs on insulin secretion in the rat

In pentobarbitone anaesthetized rats (±)-propranolol reduced the stimulatory effect of glucose, sulphonylureas, isoprenaline or phentolamine on insulin secretion. (+)-Propranolol produced similar effects to those produced by the racemate. Sotalol reduced only the insulin secretion stimulated by isoprenaline or phentolamine but not that stimulated by glucose or sulphonylureas. Complete inhibition of isoprenaline-induced hyperinsulinaemia was obtained with practolol, in a dose which was without effect on the plasma insulin elevations produced by glucose or glibenclamide. (±)-Propranolol inhibited glucose or tolbutamide-stimulated insulin secretion from chopped pancreas in vitro indicating a direct action of the drug on the pancreas. It is suggested that propranolol-induced inhibition of insulin secretion may not be entirely due to the β-adrenoceptor blocking activity of the drug.     

Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways

BACKGROUND AND PURPOSE

The G protein-coupled receptor 119 (GPR119) mediates insulin secretion from pancreatic β cells and glucagon-like peptide 1 (GLP-1) release from intestinal L cells. While GPR119-mediated insulin secretion is glucose dependent, it is not clear whether or not GPR119-mediated GLP-1 secretion similarly requires glucose. This study was designed to address the glucose-dependence of GPR119-mediated GLP-1 secretion, and to explore the cellular mechanisms of hormone secretion in L cells versus those in β cells.

EXPERIMENTAL APPROACH

GLP-1 secretion in response to GPR119 agonists and ion channel modulators, with and without glucose, was analysed in the intestinal L cell line GLUTag, in primary intestinal cell cultures and in vivo. Insulin secretion from Min6 cells, a pancreatic β cell line, was analysed for comparison.

KEY RESULTS

In GLUTag cells, GPR119 agonists stimulated GLP-1 secretion both in the presence and in the absence of glucose. In primary mouse colon cultures, GPR119 agonists stimulated GLP-1 secretion under glucose-free conditions. Moreover, a GPR119 agonist increased plasma GLP-1 in mice without a glucose load. However, in Min6 cells, GPR119-mediated insulin secretion was glucose-dependent. Among the pharmacological agents tested in this study, nitrendipine, an L-type voltage-dependent calcium channel blocker, dose-dependently reduced GLP-1 secretion from GLUTag cells, but had no effect in Min6 cells in the absence of glucose.

CONCLUSIONS AND IMPLICATIONS

Unlike that in pancreatic β cells, GPR119-mediated GLP-1 secretion from intestinal L cells was glucose-independent in vitro and in vivo, probably because of a higher basal calcium tone in the L cells.     

Chronic ritodrine treatment induces refractoriness of glucose-lowering β2 adrenoceptor signal in female mice

Adverse events in tocolytic therapy with β2-adrenergic agents compromise cardiovascular and non-cardiovascular functions, including blood glucose regulation and liver function. Here, we have examined the effects of the β2 agonist ritodrine on glucose metabolism and liver injury in mice. Under fasting conditions, ritodrine significantly increased serum insulin levels and decreased glucose concentrations. This contrasts with the β2 agonist-induced hyperglycemia observed in previous studies on humans and other animals. After 14 days of ritodrine treatment, the mice showed a decrease in the total mass of epididymal fat pads, whereas their body weights increased significantly. Chronic ritodrine treatment attenuated the glucose-lowering effect observed during acute administration. Ritodrine also significantly increased serum levels of liver enzymes, which returned to control levels after 14 days of treatment. Thus, ritodrine responsiveness changes between acute and chronic treatment, indicating that close monitoring of blood glucose and serum liver enzymes is necessary in patients with reduced glucose tolerance. The findings reported here of glucose homeostasis in mice provide a unique opportunity to understand refractoriness of β2-adrenoceptor signaling in response to β2 agonists during the course of treatment.     

The effect of selective and non-selective beta-adrenoceptor blockade, and of naloxone infusion, on the hormonal mechanisms of recovery from insulin-induced hypoglycaemia in man.

The rise in plasma adenosine-3',5'-monophosphate occurring in response to insulin induced hypoglycaemia in normal human subjects, was abolished by non-selective beta-adrenoceptor blockade but unaffected by selective beta 1-adrenoceptor blockade. This implies that the rise is secondary to beta 2-adrenoceptor stimulation. The abolition of this rise by non-selective beta-adrenoceptor blockade had no pronounced effect on the recovery from hypoglycaemia. Endogenous opiate receptor blockade with naloxone had no significant effect on the recovery from insulin induced hypoglycaemia, or the hormonal mechanisms involved.     

Gonadal steroids do not affect basal growth hormone response to naloxone in humans

Evidence has accumulated that endogenous hypothalamic opioid activity fluctuates through the menstrual cycle depending upon the ovarian steroid milieu. In fact, naloxone, the specific opiate antagonist, is more effective in producing neuroendocrine changes in the late follicular and midluteal phases of the menstrual cycle, when the functional activity of hypothalamic opiate system is high. In order to investigate a possible regulatory function of endogenous opioids on basal growth hormone (GH) secretion in humans, we studied the basal GH response to naloxone (2 mg iv as a bolus) in different phases of the menstrual cycle in ten regularly menstruating women and in eight hypogonadal (postmenopausal) females before and after estrogen treatment. This protocol was carried out to test the hypothesis that estrogens could sensitize basal GH response to opiate receptor blockade. The results do not support this view and suggest that, under basal conditions, hypothalamic opiates have minimal influence on GH secretion in humans.     

Effects of morphine and clonidine on sulphobromophthalein disposition in mice

Levels of sulphobromophthalein (BSP) in plasma and liver were elevated by the opiate, morphine, and by the alpha 2-adrenoceptor agonist, clonidine. Neither morphine, 1 mg kg-1, nor clonidine, 0.01 mg kg-1, affected BSP levels significantly. When given together at these doses, they caused BSP levels in plasma and liver to be raised. At 20 mg kg-1, the effect of morphine on BSP levels was maximal, as was that of clonidine, 1.0 mg kg-1. However, the effect of these drugs given together on plasma BSP exceeded the maximal effect of either alone. Yohimbine, an alpha 2-adrenoceptor antagonist, did not affect BSP levels, nor did the opiate antagonist, naloxone. Each of these antagonists reversed the hepatobiliary effects of its respective agonist, as shown by return of BSP levels to those of saline-treated mice. Yohimbine did not reverse morphine, nor did naloxone reverse clonidine. The additive effects of morphine and clonidine and the specificities of their respective antagonists strongly suggest the involvement of discrete receptors mediating their essentially identical hepatobiliary effects.     

Alpha 2-adrenoceptor stimulation affects total glucose utilization in isolated islets of Langerhans

Glucose utilization in isolated islets of Langerhans of the rat was determined by measuring the conversion of [5-3H]glucose (10 mM) to 3H2O. The alpha 2-adrenoceptor agonists clonidine, epinephrine, and norepinephrine in the presence of the alpha 1-adrenoceptor antagonist prazosin and the beta-adrenoceptor antagonist propranolol inhibited glucose utilization by as much as 50%. Yohimbine, an alpha 2-adrenoceptor antagonist, reversed the reduction in glucose utilization evoked by alpha 2 receptor agonists. The cholinomimetics carbachol and muscarine, and 8-bromo-cyclic GMP, but not other cyclic nucleotides, reversed the clonidine-induced suppression of glucose utilization. 3-Isobutyl-1-methylxanthine potentiated the stimulation of glucose utilization by carbachol with clonidine. In contrast, the beta-adrenoceptor agonist isoproterenol did not affect glucose utilization. Forskolin, which activates adenylate cyclase, reduced glucose utilization and did not affect the inhibitory response to clonidine. The ester phorbol 12,13-dibutyrate induced a latent reversal of the effects of clonidine. Insulin release paralleled changes in glucose utilization with alpha 2-adrenoceptor agonists. Carbachol and 8-bromo-cyclic GMP antagonized the alpha 2-adrenoceptor-induced inhibition of insulin release. During sustained insulin release (60 min), 8-bromo-cyclic AMP became a more potent modulator of secretion than 8-bromo-cyclic GMP in the presence of clonidine, although glucose utilization was not enhanced by 8-bromo-cyclic AMP.     

Insulin and lipid metabolism: new developments in drug therapy

Current treatments for non-insulin-dependent diabetes mellitus (NIDDM) remain far from ideal. The presence of both hyperinsulinaemia and resistance to insulin action in NIDDM challenges the rationale of treatments which primarily boost insulin secretion. Novel therapeutic strategies focus mainly on increasing peripheral sensitivity to endogenous insulin, an approach which has the potential not only to treat, but also to prevent NIDDM in high-risk individuals. The most promising new agents are the thiazolidinedione derivatives, in particular troglitazone. Thiazolidinediones are ligands for a specific subtype of the peroxisome proliferator activated receptor (PPAR), and decrease plasma glucose levels in both obesity and NIDDM, while at the same time reducing circulating insulin and free fatty acid levels. The current development status of these agents is reviewed, along with an assessment of their potential in the prevention and treatment of diverse pathophysiological states characterised by insulin resistance, including atherosclerosis and polycystic ovarian disease. Reference is made to the current status of other experimental agents including hydantoin derivatives, (3)-adrenoceptor agonists, and inhibitors of lipolysis.